Project Summary Traumatic brain injury (TBI) is a serious health care problem with staggering individual and societal costs. Secondary elevation of intracranial pressure (ICP) is a major contributing factor in exacerbated TBI-initiated morbidity in the human population. However, apart from the well-known relationship between high ICP and hematoma/contusion expansion and/or ensuing global ischemia due to reduced CPP, virtually nothing is known regarding the diffuse pathologies mediated by ICP. This lack of knowledge is highlighted by the limited success of current therapies in overcoming the predisposition for negative outcomes associated with elevated ICP post TBI. These issues have sparked intense debate over the clinical efficacy of such ICP/CPP-based treatment strategies while also calling into question the current threshold of 20mmHg as a target for therapeutic intervention for elevated ICP post-TBI. Therefore, the long-term goal of this study is to investigate ICP-mediated diffuse pathologies following TBI. Recently it was found that sub- acute neuronal membrane poration is exacerbated in animals sustaining TBI and manually elevated ICP, without attendant ischemia due to low CPP. Further there was suggestion that this pathology, extends for days to weeks following injury, potentially via a cathepsin-B-mediated pathway, and is linked to ICP-mediated chronic behavioral morbidity. In accordance with these findings the current project aims to 1) elucidate the pathological progression of TBI-induced sub-acute cortical neuronal membrane poration and the involvement of cathepsin-B-mediated molecular mechanisms in this pathology, 2) investigate the effect of secondary ICP elevation on neuronal pathology and behavioral morbidity following diffuse TBI and 3) determine if novel therapies targeting either inhibition of the cathepsin-B pathway or induction of membrane resealing could alleviate exacerbated pathology and morbidity in the face of elevated ICP. These aims will be addressed using a novel rat model of ICP elevation following diffuse TBI in concert with fluorescent tracer infusion paradigms that allow for the identification and isolation of sub-acutely porated neurons. This animal model will be paired with microscopic, molecular, and behavioral assessments to evaluate ICP-mediated diffuse neuronal pathology and its link to morbidity following TBI. Together, these studies are anticipated to greatly advance understanding of the pathologies modulated by secondary elevations of ICP following TBI and could directly translate to enhanced clinical practice for the treatment of elevated ICP in TBI patients.